Hyperglycemia and circadian disruption lead to retinal dysfunction in a stabilized colony of the fat sand rat Psammomys obesus

Purpose: The Fat Sand Rat ( Psammomys obesus ) recapitulates several features of human pre-proliferative diabetic retinopathy, but data are restricted to wild animals, incompatible with stringent biomedical research criteria. To overcome this barrier, we characterized retinal changes in a colony of P. obsesus maintained under strictly controlled housing conditions. Methods: Animals were maintained on low or high caloric energy diets, and raised under either standard (12 h light/12 h dark) or shortened (5 h light/5 h dark) photoperiods. Visual responses were tested by electroretinography, while structural/molecular changes were assayed by immunochemistry and molecular biology (RNAseq and qPCR). Results: Whereas high calorie diet alone did not induce hyperglycemia, coupled with short photoperiod >80 % animals developed severe hyper-insulinemia by 15 weeks, and 16 % animals further developed hyperglycemia. In these groups, electroretinography showed significant declines in visual responses in both hyperinsulinemic and hyperglycemic animals, especially in photopic (cone) responses. Transcriptomics analysis of hyperglycemic compared to low caloric controls revealed major upregulation in pathways involved in glial activation, extracellular matrix remodeling, inflammation, cytokine production, partial ischemic responses and angiogenesis. Western blotting against rhodopsin and cone opsin also showed decreased levels in both groups, overall decreases being greater for cones than rods in hyperglycemic animals. Conclusions: P. obesus maintained in rigorously monitored captive conditions, albeit showing attenuated responses to dietary overload compared to wild counterparts, nevertheless do develop some retinal features of diabetic retinopathy-like degeneration. Such a colony with known sanitary status opens their broader use for biomedical research.